cesnicabtagene autoleucel (ARI0002h)

Ide-cel and Cilta-cel are CAR-T cells directed against BCMA, having received FDA approval for RRMM based on the Phase 2 KarMMa and CARTITUDE trials, respectively...Additional anti-BCMA targeted medicines, including LCAR-B38M, completely humanized CAR-T (FHVH-T), P-BCMA-ALLO-1, ALLO-715, and anti-BCMA CAR-NK, provide promising treatment options. Moreover, the anti-CD19 Fast-CAR, designed to shorten production time, and PHE885, which possesses in-vivo proliferation capability, are regarded as very efficacious...The development of academic CAR-Ts such as ARI0002h, HBI0101, eque-cel, zevor-cel, anito-cel, and Sleeping Beauty (utilizing a non-viral vector) have importance due to their accessibility and cost-effectiveness...To overcome these issues, strategies are being implemented, including combination therapy, the incorporation of gamma-secretase inhibitors etc. In conclusion, CAR-T treatments have evolved into an effective therapy modality being anticipated to be utilized in earlier phases in the future. Gene editing (CRISPR) method contributes to the future perspective.

P2, N=15, Not yet recruiting, Cell and Tissue Therapies WA, Royal Perth Hospital, East Metropolitan Health Service

However, this improvement was not significant compared to ARI0002h (p = 0.07). This study failed to demonstrate a significant benefit of TIGIT-blockade on ARI0002h cells despite using three different approaches, suggesting that targeting a single immune checkpoint may be insufficient.

This study investigates the role of metabolites and gut microbiota in clinical outcomes in patients treated with the humanized BCMA-directed CAR-T therapy, ARI0002h...These multimodal profiles were integrated into response models, including one that identified patients likely to achieve a complete response by day 100 and 180 post-infusion. These findings suggest that metabolites and gut microbiota correlate with CAR-T cell therapy responses and can be a valuable tool for risk assessment.

Based on specificity, efficacy, and loss of the target antigen, CARLY3 represents a potential novel CAR treatment for NHL.

We optimized different dual-targeting approaches, including co-transduction of two lentiviral vectors, bicistronic, tandem, loop and pool strategies, based on our academic anti-CD19 (ARI0001) and anti-BCMA (ARI0002h) CAR-T cells. ARI0003 CAR-T cells were effectively manufactured under Good Manufacturing Practice conditions, with reduced risk of genotoxicity compared to other dual-targeting approaches. A first-in-human phase I clinical trial (CARTD-BG-01, NCT06097455) has been initiated to evaluate the safety and efficacy of ARI0003 in NHL.

Lymphodepletion (LD) with cyclophosphamide and fludarabine was used...Tocilizumab and steroids were administered in 68% (mainly for persistent grade 1 CRS) and 30% of pts, respectively... Results from 30 additional pts and a longer follow-up of the first cohort confirm the deep and durable responses obtained with ARI0002h. The booster dose may be partially responsible for the improvement of responses over time and exhaustion may play a role in relapse.

To shed some light on specific transcriptomic programs activated after CAR-T cell administration, we interrogated longitudinal samples of CAR-T cells collected from patients enrolled in CARTBCMA-HCB-01 (NCT04309981) and academic clinical trial in patients with RRMM (Oliver-Caldes A, et al... Overall, our analysis combining scRNA-seq/scTCR-seq with novel machine learning models, allowed us to characterize key transcriptional differences observed between patients, infusion products and in vivo infused CAR-T, as well as between CAR-T according to their location (PB vs. BM). Importantly, our results identify IL10 as a regulatory mechanism promoting CAR-T cell dysfunction, representing a potential target to be modulated for the development of improved CAR-T therapies for MM.

To shed light on the potential mechanisms driving CAR-T cell persistence we performed longitudinal transcriptomic analysis, at single cell level, of CAR-T cells from a patient enrolled in CARTBCMA-HCB-01 clinical trial (NCT04309981) (Oliver-Caldes A, et al... Our analysis clearly showed that most CAR-T cells after administration presented expression of key markers related to T cell memory and survival without clonal expansion, suggesting that memory induction is crucial for long-term persistence. Interestingly, prior to tumor relapse, we observed reactivation of CAR-T cell with the enrichment of effector and activation signatures, and GRN analysis identified FOS and NR4A2 regulons as potential drivers involved in CAR-T cell reactivation. Overall, scRNA-seq/scTCR-seq coupled with novel machine learning models provides relevant mechanistic insights that could uncover useful targets to be modulated for the development of long-term persistent CAR-T cells.

ARI0002h administered in a fractioned manner with a booster dose after 3 months can provide deep and sustained responses in patients with relapsed or refractory multiple myeloma, with a low toxicity, especially in terms of neurological events, and with the possibility of a point-of-care approach.

At our institution, we have developed an academic BCMA-BBζ CART product (ARI2h; NCT04309981) for relapsed/refractory MM patients with encouraging results... This is the first bispecific BCMA/CD229 CART cell that adequately controls BCMA-expressing and non-expressing myeloma cells. This approach could mitigate disease escape due to biallelic loss of BCMA.

CAR-T cells were FACS-isolated from infusion products (IP) as well as from bone marrow (BM) and peripheral blood (PB), at different times after cell infusion (1 and 3 months), from three MM patients enrolled in the academic clinical trial assessing ARI0002h... Overall, our data show that multiomic analysis are useful tools to characterize CAR-T cell dynamics after infusion, that presented different characteristics regarding their location (PB vs BM) and a heterogeneous behavior within the patients. Moreover, GRN analysis at single cell level offers an important tool to understand mechanisms modulating CAR-T cell response and to identify possible mechanisms of relapse.